FDA-approved inhibitors of HIV-1 IN belong to a class of drugs called integrase strand transfer inhibitors (INSTIs), due to their ability to preferentially block the enzyme's strand transfer (ST) reaction as compared to the enzymes 3'-processing (3'-P) reaction. Unfortunately, mutant forms of IN arise that lead to clinical resistance against these INSTIs. This adds impetus to a continuing need to develop next-generation agents that have the ability to retain high antiviral efficacy against emerging strains of INSTI-resistant virus. Utilizing my laboratory's design and synthetic capabilities, we have teamed with pharmacologists (Dr. Yves Pommier, NCI), virologists (Dr. Hughes, NCI) and structural biologists (Dr. Cherepanov, the Francis Crick Institute, UK) to develop new INSTIs. In collaboration with Dr. Cherepanov we have obtained co-crystal structures of our best inhibitors bound to the prototype foamy virus (PFV) intasome (multimeric integrase with DNA substrate and metal cofactor). Using a single-round replication assay, Dr. Hughes evaluated DTG and BIC, the leading second-generation FDA-approved INSTIs and a collection of our best inhibitors against a broad panel of INSTI-resistant mutants. Two of our inhibitors showed superior antiviral profiles than DTG and BIC across the panel of mutants. Our collaboration has recently been extended to include the Salk Institute laboratory of Dr. Dmitry Lyumkis, the NIDDK laboratory of Dr. Robert Craigie and the University of Colorado laboratory of Dr. Mamuka Kvaratskhelia to obtain cryo-EM structures of our inhibitors bound to the catalytic site of HIV IN with DNA substrate and metal cofactor. To date, a number of high-resolution cryo-EM structures have been solved. Finally, a collaboration has been initiated with the Imperial College London laboratory of Dr. Goedele Maertens to examine a diverse selection of our IN inhibitors against human T-cell leukemia virus type 1 (HTLV-1) and a number of our synthetic constructs show significant potency against this target.